This invention relates to a pharmaceutical composition comprising a tungsten (VI) compound for use as an insulin mimicker, and to a method of lowering blood sugar in a mammal using the pharmaceutical composition.
Diabetes mellitus is a major global health problem which is recognised by the World Health Organisation to be reaching epidemic proportions. It is now the fourth leading cause of death in most developed countries and a disease that is increasing rapidly in countries undergoing industrialisation. Estimates of worldwide diabetes prevalence have increased from 30 million in 1985 to more than 100 million in 1994. Diabetes mellitus is a disease caused by defective carbohydrate metabolism and characterized by abnormally large amounts of sugar glucose in the blood and urine. Diabetes mellitus can eventually damage the eyes, kidneys, heart, and limbs, and can endanger pregnancy.
Diabetes mellitus is usually classified into two types. Type 1, or insulin-dependent diabetes mellitus (IDDM), formerly called juvenile-onset diabetes, which occurs in children and young adults, has been implicated as one of the autoimmune diseases. Rapid in onset and progress, it accounts for about 10 to 15 percent of all cases. Type 2, or non-insulin-dependent diabetes mellitus (NIDDM), formerly called adult-onset diabetes, is usually found in persons over 40 years old and progresses slowly. Often it is not accompanied by clinical illness in its initial stages and is detected instead by elevated blood or urine glucose levels.
Diabetes is considered a group of disorders with multiple causes, rather than a single disorder. The human pancreas secretes a hormone called insulin that facilitates the entry of the sugar glucose into tissues of the body and its utilization, thus providing energy for bodily activities. In a person with diabetes, however, the entry of glucose is impaired, a result either of a deficiency in the amount of insulin produced or of altered target cells. Consequently, sugar builds up in the blood and is excreted in the urine. In the Type 1 diabetic, the problem is almost always a severe or total reduction in insulin production. In the Type 2 diabetic, the pancreas often makes a considerable quantity of insulin, but the hormone is unable to promote the utilization of glucose by tissues.
With adequate treatment most diabetics maintain blood-sugar levels within a normal or nearly normal range. This enables them to live normal lives and prevents some long-term consequences of the disease. For the Type 1 diabetic with little or no insulin production, therapy involves insulin injections. For Type 2 diabetics, most of whom are at least moderately overweight, the basics of therapy are diet control, weight reduction, and exercise. Weight reduction appears to partially reverse the condition of insulin resistance in the tissues. If a patient's blood-sugar level is still high, the physician may add insulin injections.
Besides the discomfort associated with its administration by injection, the problem of controlling the dose of insulin also exists. The hypoglycemia produced by an insulin overdose, depending on its importance, may lead to tremulousness, cold sweat, piloerection, hypothermia, and headache, accompanied by confusion, hallucinations, bizarre behaviour, and ultimately, convulsions and coma. Therefore, it would be very advantageous to have an insulin substitute not producing hypoglycemia in case of accidental overdose.
Given that insulin is only active when administered by injection, and that the administered dose must be controlled, it has been clearly stated for years that an oral active insulin-substitute, especially if it does not produce hypoglycemia of overdose, would greatly decrease diabetic patients' discomfort and risk.
Unfortunately, so far the therapeutical problem of having an adequate oral treatment of diabetes mellitus is still unsolved. In recent years, several inorganic compounds have been described which mimic the effects of insulin, both in vivo and in isolated cells and tissues. These include some vanadium compounds (cf. Heyliger et al., "Effect of vanadate on elevated blood glucose and depressed cardiac performance of diabetic rats", Science 1985, vol. 227, pp. 1474-7); selenate (cf. McNeill et al., "Insulinlike effects of sodium selenate in streptozotrocin-induced diabetic rats", Diabetes 1991, vol. 40, pp. 1675-8), and lithium salts (cf. Rodriguez-Gil el al., "Lithium restores glycogen synthesis from glucose in hepatocytes from diabetic rats", Arch. Biochem. Biophys. 1993, vol. 301, pp. 411-5). From all these vanadium, selenium and lithium compounds, so far, only vanadium compounds have been proposed as insulin-mimicker drugs for the oral treatment of diabetes (cf. Schechter et al., "Vanadium salts and the future treatment of diabetes", Endeavour 1993, vol. 17, pp. 27-31). The vanadium derivatives which have been studied as insulin-mimickers include: alkaline earth metal or alkaline metal vanadate (vanadium in its +5 oxidation state combined with oxygen, especially orthovanadate VO.sub.4.sup.3-), vanadyl VO.sup.2+ salts and peroxovanadium complexes (cf. U.S. Pat. No. 4,882,171).
Vanadium compounds are currently undergoing clinical trials in Europe and America. But oral administration of vanadium compounds has the drawback of toxicity at effective doses. Administered concentrations must be close to the toxic level, if the insulin-mimetic effects in animals are to be achieved. Vanadium-treatment is always accompanied by marked negative side effects that are independent of the chemical form of vanadium used (cf. Domingo et al., "Oral vanadium administration to streptozocin-diabetic rats has marked negative side-effects wich are independent of the form of vanadium used", Toxicology 1991, vol. 66, pp. 279-87.). Remarkable signs of vanadium compounds toxicity are observed at all the doses that are able to lower blood glucose, including a significant mortality rate. In summary, clinical trials of vanadium compounds have been criticized on the grounds of the high toxicity at therapeutical doses, up to the point that some authors have claimed that vanadium is not a viable option to treat human diabetes. A recent letter to Diabetes (1994, vol. 43, p. 1270), stated that "With the possible exception of cytotoxic drugs, it must be almost unprecedented for an agent with such an impressive record of morbidity and mortality to reach the point of being tested in humans."
In summary, so far there is no satisfactory solution to the problem of having an insulin-mimicker drug for oral treatment of diabetes mellitus. To be pharmaceutically acceptable, such a drug simultaneously must have a high sugar-lowering activity and a low oral toxicity at effective doses. Toxicity must be low not only short-term but also long-term, because diabetes mellitus is a chronic disease. It would be very advantageous also, that the drug does not produce hypoglycemia in case of accidental overdose, which is a problem of the administration of insulin by injection.